Methylation of substituted uracil



Patented Feb. 20, 1951 METHYLATION OF SUBSTITUTED URACIL Frederick Comte, Kirkwood, Mo., assignor to Monsanto Chemical Company, St. Louis, Mo., a

corporation of Delaware N Drawing. Application February 28, 1949, Serial No. 78,885

7 Claims. (Cl. 260-260) This invention relates to certain 1,3-dimethyl derivatives of amino and formamido substituted uracil; more specifically this invention relates 'to an improved process for the production of 1,3- dimethyl-4-formamido-5-amino uracil or 1,3-dimethyl-4-amino-5-formamido uracil having the following respective formulas:

This material is an important intermediate for the preparation of various pharmaceuticals. The most convenient method of preparing 1,3-dimethl-4-formamido-5-amino uracil or 1,3-dimethyl-4-amino-5-formamido uracil would be by the methylation of 4-formamido-S-amino-uracil or 4-amino-5-formamido uracil having the following respective formulas:

However, the reactivity of this material towards the common methylating agents has been found to be extraordinarily unique and unpredictable, so much so that a practical and economically satisfactory commercial process for their controlled methylation has not been heretofore realized. Thus methylation with methyl chloride has been found to require the use of exceedingly high pressures in order that a satisfactory yield of the desired 1,3-dimethyl derivative be produced. Such a. process requires the use of costly pressure equipment which, in addition to being able to withstand the high pressures developed, must also be capable of resisting the highly corrosive action of the hydrochloric acid formed in the reaction. While methyl iodide as a methylating agent has been found to produce the desired product under ordinary pressures, yet similar corrosive conditions are created and the excessive cost or methyl iodide renders its use economically prohibitive. One of the most desirable methylating agents is dimethyl sulfate. Its low cost, availability, and ease of handling make it particularly attractive as a commercially feasible methylating agent. However, all attempts in the past to obtain 1,3-dimethyl-4-formamido-5-amino uracil or 1,3-dimethyl-4-amino-5-formamido uracil by the methylation of 4-formamido-5-amino uracil or 4-amino-5-formamido uracil with dimethyl sulfate have been unsuccessful.

It is an object of this invention to provide an improved process for the production of 1,31-dimethyl-4-formamido-5-amino uracil or Lil-dimethyl-4-amino-5-formamido uracil.

It is a further object of this invention to provide a method for the production of 1,3-dimethyl-4-formamido-5-amino uracil or Lil-dimethyl- 4-amino-5-formamido uracil by the methylation of 4-formamido-5-amino uracil or 4-amino-5- formamido uracil with dimethyl sulfate.

Further objects will become apparent from the description of the novel process of this invention and the claims.

It has now been discovered that certain formamido-amino uracils, namely, 4-formamido-5- amino uracil or l-amino-fa-forrnamido uracil and its alkali metal salt may be conveniently and easily methylated with dimethyl sulfate to form 1,3-dimethyl-4-formamido-5-amino uracil or 1,3- dimethyl-4amino-5-formamido uracil respectively when the methylation is carried out in a carefully controlled and limited pH range. Thus, it has been discovered that 1,3-dimethy1-4-formamido-5-amino uracil or 1,3-dimethyl-4-amino- 5-formamido uracil is produced in high yields and exceptional purity when the correspondingly substituted formamadio-amino uracil or its alkyl metal salt is methylated in an aqueous medium by the simultaneous addition of an excess of dimethyl sulfate and an aqueous alkaline solution with constant agitation and at such a rate so as to maintain the reaction mixture at a pH in the range of from7.0 to 11.0 and a temperature in the range of from 0 C. to C.

In carrying out the novel process of this invention, the temperature may be maintained anywhere within the range of from 0 C. to 100 C. However for practical purposes, the preferred range is from about 20 C. to about '50" C.

It is of course desirable to have as high a concentration as possible of the formamido-amino uracilpr its sodium salt in the aqueous suspension in order to obtain maximum yield per cycle. Inasmuch as the solubility limit of either of these -tion.

3 materials may be exceeded so that the reaction medium is part suspension and part solution, the concentration utilized is governed chiefly by the viscosity of the resultant suspension which will permit efiicient agitation. This in turn will be governed by the temperature of the reaction and the natureof the equipment and means-ofragitas excess of about 25% by weight of the formamidoamino uracil generally produce suspensions.-

which are too thick to agitate, efiiciently with ordinary equipment.

Either the formamido-amino uracil-or itsalkali, metal salt may be utilized in this reaction; The.-v

alkali metal salt may be conveniently prepared by merely reacting one molecular. proportion of the formamido-amino uracil with an approxie mately one molecular proportion of an alkali metal hydroxide in an aqueous medium.

In carrying out this methylation reaction, it is essential that the dimethyl; sulfate and. aqueous. alkaline solution be added simultaneously and. at such a rate so as to maintain thepH of the.

reaction mixture-in the range of 7-.0-to 11.0 and preferably in therange of 9.0. to 10.0., LowerpH conditions significantly decrease the rate, of the. reaction. while higher pH conditions cause the. Obviously therateof. addition. of the dimethyl sulfate and theaqueous. alkaline solution; neednot: and probably will not.- The expression simultaneous ad.-

formation of by-products.

be identical. ditioni is used in its practical sense rather than itsliteral sense, meaning the additionof an. alka.-

line solution to the reactionmixture during the methylation reaction which is" taking placeduring the addition of the dimethyl sulfate-in such amanner and rate to maintain the, pH in theprescribed'range. Thus, it ispossiblefor the-ad.- dition of the alkaline solution to. beat times intermittent rather than continuous aslong asthe. pH is maintained in the prescribed range;

The pH of the reactionimixture; may beiasceretained by any of the convenient methods well known to those skilled in the art with probably the most practical method being by means of continuous potentiometric measurements.

In order to particularly prescribe the' nature-.of

the aqueous alkaline solutionutilizedin thisre-- action, and the quantity of reactants, it is 118085.- sary to consider the theoretical aspects; of the. reactions that take place. When dimethyl sul fate, (Cl-192804, is added to formamido-aminouracil, one methyl group of the dimethyl sulfate. attaches to the uracilring andmethyl acid sull- Thus to form the: di-

fate, filial- $04, remains. methyl substituted formamido-amino uracil there would theoretically be necessarythe addition of: two molecular proportions of dimethyl sulfatefor.

each molecular proportion of formamidoraminov uracil thereby forming two molecular'proportions of methyl acid sulfate.

may proceed. However, theaddition' ofran alkacline solution promotes the hydrolysis of dimethyl It has been found. that concentrations in.

This material is very: highly acidic and must be neutralizedzby theacle dition of an alkaline solution to raise the: pI-Iiinto: the aforescribed range in order-that thereaction.

' The concentrationof such solutions may be varied sulfate thereby decreasing the amount of. di-- methyl sulfate available. for' the methylation of the uracil ring. Consequently, an excess of. (iimethyl sulfate over the theoretical two, molecular. proportions must be utilized'to obtain satisfactory yields. The amount of the excess: of dimethyl sulfate is necessarily dependent to a great extent. on the reaction conditions'within the prescribed It has been found that generallwfrom imits.

over a: wide range, The highest concentrations that still-permit accurate pH control are preferred as, less. volume. of solution is necessary. Aqueous alkaline solutions containing from about 20% to about 50% of the alkali metal hydroxides have been fou'nd' to be quite advantageous because of their obvious economical advantages and ease of; handling;

The" 1,3 dimethyl-4-formamido5-amino uracil or the l,3-dimethyl-4:-amino-5formamido uracil formed in the reaction may be recovered by any of the methods" well known to those skilled. in the art; The most convenient method is that of merely cooling the reaction mixture and filtering the crystall zed 1,3-dimethyl derivative, washing with water until free from sulfates, and then drying. The mother liquor from the reaction mixture may be further evaporated, preferably under reduced pressure, to obtain the small amount of the 1,3-dimethyl derivative retained.

The following examples are illustrative of the novel process of this invention:

ExampleI 34.0 g.. of 4 -f0r.mamido-5-aminov uracil was added to 400ml of water having dissolved therein.

19.7 g. of a 40.7% sodium hydroxide solution.

The temperature of this mixture was adjusted to about 35 C. With constant agitation, 55 ml. of. dimethyl sulfate was slowly added to the reaction mixture while simultaneously adding about.

40' g. of" a 40.7% sodium hydroxide solution at such a rate as to maintain a pH in the reaction mixture of from about 9.0 to about 10.0 as measured potentiometrically. actants had been added, the reaction mixture was cooled to 25 C. and the crystals of 1,3-dimethyl-4-formamido 5-amino uracil filtered. The crystals were washed with wateruntil free from sulfates. By evaporation of the mother liquor the remaining crystals of the 1,3-dimethyl- 4-formamido-5-amino uracil were obtained. The crystals were then dried at about C. thereby obtaining 29.4 g. offine, white, needle crystals of 1,3rdimethyl-4-formamido-5-amino uracil hav-- 111g. adecompositionpoint; of about 264 C. The. yield was about 7.5%.- based. on 4.-formamido.--

5-amino uracil.

Example II 51 g. of 4,-formamidoz-5-amino uracil was slurried.with-constant-agitation at a temperature of about 40'C. with about 500 ml. of 320. About 84 ml. ofv dimethyl, sulfate and 88 g. of 41.1%. sodium hydroxide were: slowly. added 'simultaneously to thereaction mixture, keeping the addition of the sodium hydroxide solution at such a rate as to maintain a pH in the range of from 8.5 to 10.5. reaction mixture was cooled to about 0 C. and thewhite crystals of 1,3 dimethyll-formamido- After; all ofthe reactants had-been added, the- After. all of the re- I Example III 100 g. of 4-amino-5-formamido uracil was slurried with about 900 m1. of water. With constant agitation and while maintaining a temperature in the range of from 20 to 35 C. and a pH in the range of from 9.0 to 10.0, 1'70 ml. of dimethyl sulfate and about 176 g. of a 4.0% sodium hydroxide solution was slowly added to the reaction mixture.

After the reactants had been added an excellent yield of substantially pure crystals of 1,3- dimethyl-4-amino-5-formamido uracil was recovered from the reaction mixture in the manner described in Example I.

What is claimed is:

1. In the process for the production of certain 1,3-dimethyl substituted uracils the step comprising the addition with agitation of dimethyl sulfate to an aqueous medium containing a substituted uracil selected from the group consisting of 4-formamido-5-amino uracil, 4-amino-5- formamido uracil and their alkali metal salts in the ratio of at least two molecular proportions of the dimethyl sulfate per molecular proportion of the selected substituted uracil while simultaneously adding an aqueous alkaline solution so as to maintain the reaction mixture at a pH within the range of from 7.0 to 11.0 and a temperature in the range of from 0 C. to 100 C.

2. In the process for the production of certain 1,3-dimethyl substituted uracils the step comprising the addition with agitation of dimethyl sulfate to an aqueous medium containing a substituted uracil selected from the group consisting of 4-formamido-5-amino uracil, 4-amino-5- formamido uracil and their alkali metal salts in the ratio of at least two molecular proportions of the dimethyl sulfate per molecular proportio of the selected substituted uracil while simultaneously adding an aqueous alkaline solution so as to maintain the reaction mixture at a pH within the range of from about 9.0 to 10.0 and a temperature in the range of from 20 C. to about C.

3. The process as described in claim 21, wherein the substituted uracil is 4-formamido-5- amino uracil.

4. The process as described in claim 2, wherein the substituted uracil is 4-amino-5-formamido uracil.

5. The process as described in claim 2, wherein the substituted uracil is the alkali metal salt of 4-amido-5-amino uracil.

6. The process as described in claim 2, wherein the substituted uracil is the alkali metal salt of 4-amino-5-formamido uracil.

7. The process as described in claim 2. wherein the aqueous alkaline solution is an aqueous solution of an alkali metal hydroxide.

FREDERICK COMTE.

REFERENCES CITED The following references are of record in the file of this patent:

Chemical Abstracts, 39, 69'? (1945), [citing Rubstov, J. Gen. Chem. (USSR), 13, 710-716 (1943) (English Summary) Shepherd et al., J. Org. Chem, 12, 453 (1947).

Bobranski et al., J. Am. Pharm. Assoc, Science Edition, 3'7, 62-64 (Feb. 1948).

Certificate of Correction Patent No. 2,542,395 February 20, 1951 FREDERICK COMTE It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:

Column 4:, line 75, strike out After all of the reactants had been added, the and insert the same below 8.5 to 10.5. in line 72; column 6, line 10, after the Word from insert about; line 20, strike out amide and insert instead formamz'do;

and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 24th day of April, A. D. 1951.

[SEAL] THOMAS F. MURPHY,

Assistant Oommissz'oner of Patents. 

1. IN THE PROCESS FOR THE PRODUCTION OF CERTAIN 1,3-DIMETHYL SUBSTITUTED URACILS THE STEP COMPRISING THE ADDITION WITH AGITATION OF DIMETHYL SULFATE TO AN AQUEOUS MEDIUM CONTAINING A SUBSTITUTED URACIL SELECTED FROM THE GROUP CONSISTING OF 4-FORMAMIDO-5-AMINO URACIL, 4-AMINO-5FORMAMIDO URACIL AND THEIR ALKALI METAL SALTS IN THE RATIO OF AT LEAST TWO MOLECULAR PROPORTIONS OF THE DIMETHYL SULFATE TWO MOLECULAR PROPORTION OF THE SELECTED SUBSTITUTED URACIL WHILE SIMULTANEOUSLY ADDING AN AQUEOUS ALKALINE SOLUTION SO AS TO MAINTAIN THE REACTION MIXTURE AT A PH WITHIN THE RANGE OF FROM 7.0 TO 11.0 AND A TEMPERATURE IN THE RANGE OF FROM 0* C. TO 100* C. 